The usefulness of tranexamic acid for bleeding symptoms of chronic consumptive coagulopathy complicated by aortic disease: a single-institute, retrospective study of 14 patients.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that blocks lysine-binding sites on the profibrinolytic enzyme plasminogen. Aortic diseases with chronic consumption coagulopathy may lead to disseminated intravascular coagulation (DIC) and cause fatal bleeding. Although the use of antifibrinolytic agents in DIC is generally not recommended due to enhanced fibrin deposition risking thrombotic symptoms, the efficacy of TXA has been reported in several cases of DIC with aortic diseases. However, the efficacy and safety of TXA for bleeding symptoms of chronic consumption coagulopathy with aortic diseases have not been studied in detail. METHODS: We evaluated the efficacy of TXA in 14 patients with chronic consumptive coagulopathy due to aortic disease complicated by bleeding symptoms. Changes in coagulation and fibrinolysis parameters from baseline were analyzed with Wilcoxon matched-pairs signed-rank tests, excluding missing values. Kaplan-Meier curves were used to analyze overall survival. RESULTS: Median age was 78.5 years (range, 66-89 years) and median observation period was 448 days (range, 0-2282 days). Twelve patients had chronic renal failure and 1 patient had chronic liver failure. Before starting treatment, median Japanese Ministry of Health and Welfare DIC diagnostic criteria score was 8 (range, 4-11) and median platelet count was 64 × 109/L (range, 25-97 × 109/L). Twelve patients underwent evaluation of bleeding symptoms after introduction of TXA, and 10 of those 12 patients showed improved bleeding tendencies within 30 days (median, 5.0 days). One patient with chronic liver failure showed worsening of bleeding symptoms. Although only one patient was initiated TXA in combination with anticoagulants, no significant worsening of thrombotic events was observed within 30 days. CONCLUSIONS: TXA therapy appears effective against chronic consumptive coagulopathy with bleeding due to aortic disease, with few side effects.

A case of sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: long-term observation of neurological symptoms after autologous stem-cell transplantation.

A 47-year-old woman presented with progressive limb weakness. A neurological examination revealed proximal dominant symmetrical muscle weakness in her limbs, and electromyography revealed complex repetitive discharges and short motor unit potentials with positive sharp waves in the biceps. We observed early recruitment in the quadriceps, and laboratory tests revealed normal creatine kinase. Serum protein electrophoresis showed monoclonal IgG-lambda, but the bone marrow aspiration specimen was normal. A muscle biopsy revealed nemaline rod accumulations in the muscle fibers; based on the results, we diagnosed the patient with sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS). We administered repeated intravenous immunoglobulin, but her limb weakness continued, and she developed a restrictive ventilatory defect. The patient received melphalan, followed by autologous stem-cell transplantation (ASCT). Her upper extremity strength and respiratory capability improved within one year after ASCT; however, it was not until six years after ASCT that her atrophied lower extremities strengthened. A discrepancy in the timeline of treatment response between the upper or respiratory muscles and the atrophied lower limb was characteristic in the patient, suggesting that the efficacy of ASCT on SLONM-MGUS should be evaluated in the long term, especially in severely atrophied muscles. In addition, this case showed that ASCT for SLOMN-MGUS is an effective treatment option in Asian populations.

[Leukemic pulmonary infiltration diagnosed by sputum Giemsa-staining].

A 54-year-old man with acute myeloid leukemia (AML) underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched unrelated donor in nonremission status. Bone marrow aspiration performed on day 14 showed that the patient had achieved complete remission; however, he relapsed on day 28. The patient developed a wet cough, and chest computed tomography performed on day 27 revealed pneumonia. Because pneumonia developed along with the leukemic relapse, we suspected that it was due to pulmonary leukemic infiltration (PLI). Giemsa-stained sputum showed some blast cells and fluorescence in situ hybridization indicated that the patient had monosomy 7, which was also detected in bone marrow blasts. Though we prescribed hydroxycarbamide and decreased tacrolimus rapidly, AML progressed and led to the patient's death on day 45. Histopathological findings of the autopsy performed the next day showed diffuse alveolar damage in both lungs. The blast cells were packed in blood vessels of alveolar septa and were also seen in alveoli. PLI was diagnosed pathologically. In conclusion, our case demonstrates that Giemsa stain of sputum is useful in quick diagnosis of PLI without invasive examination.

The stability of initial tacrolimus concentration following allogeneic hematopoietic stem cell transplantation reduces the risk of acute GVHD.

BACKGROUND: Early tacrolimus (TAC) concentrations correlate with the risk of acute graft-versus-host disease (aGVHD); however, whether the variability of early TAC concentrations after allo-HSCT governs the occurrence of aGVHD remains unknown. Here, we evaluate the correlation between the intrapatient variability (IPV) of initial TAC concentrations and the development of aGVHD. METHODS: We retrospectively assessed 202 patients who underwent allo-HSCT and received standard GVHD prophylaxis by continuous intravenous (iv) infusion of TAC and iv methotrexate. IPV was calculated by using the % coefficient of variation in the initial 4 weeks. RESULTS: With median follow-up duration of 20.7 months, 24 patients were diagnosed with grades II-IV aGVHD. Overall survival (OS) and relapse at 12 months after allo-HSCT were 70.6% (95% confidence interval [CI], 63.7%-76.4%) and 18.9% (95% CI, 13.0%-24.4%), respectively. When IPV was categorized into two groups (high: ≥9.5%; low: <9.5%), the cumulative incidence of grades II-IV aGVHD was greater in the IPV-high group at week 3 (odds ratio: 4.15; 95% CI, 1.37%-12.6%, P = .01). No significant differences were observed in OS and relapse between the two groups. CONCLUSION: We concluded that adjusting early TAC concentration stable may reduce aGVHD after allo-HSCT without affecting the relapse rate.

Transcriptomic and Proteomic Analyses Reveal the Potential Mode of Action of Chondrocyte Sheets in Hyaline Cartilage Regeneration.

Chondrocyte sheet transplantation is a novel and promising approach to treating patients who have cartilage defects associated with osteoarthritis. Hyaline cartilage regeneration by autologous chondrocyte sheets has already been demonstrated in clinical research. In this study, the efficacy of polydactyly-derived chondrocyte sheets (PD sheets) as an allogeneic alternative to standard chondrocyte sheets was examined using an orthotopic xenogeneic transplantation model. In addition, the expression of genes and the secreted proteins in the PD sheets was analyzed using a microarray and a DNA aptamer array. The efficacy of PD sheets with respect to cartilage defects was assessed using histological scores, after which the expressions of genes and proteins exhibiting a correlation to efficacy were identified. Enrichment analysis of efficacy-correlated genes and proteins showed that they were associated with extracellular matrices, skeletal development, and angiogenesis. Eight genes (ESM1, GREM1, SERPINA3, DKK1, MIA, NTN4, FABP3, and PDGFA) exhibited a positive correlation with the efficacy of PD sheets, and three genes (RARRES2, APOE, and PGF) showed a negative correlation for both transcriptomic and proteomic analyses. Among these, MIA, DKK1, and GREM1 involved in skeletal development pathways and ESM1 involved in the angiogenesis pathway exhibited a correlation between the amount of secretion and efficacy. These results suggest that these secreted factors may prove useful for predicting PD sheet efficacy and may therefore contribute to hyaline cartilage regeneration via PD sheets.

Prediction of clinical outcome by controlling nutritional status (CONUT) before allogeneic hematopoietic stem cell transplantation in myeloid malignancies.

Malnutrition before allogeneic hematopoietic cell transplantation (allo-HCT) is associated with poor clinical outcomes. Herein, we evaluated the predictive value of controlling nutritional status (CONUT) in patients undergoing allo-HCT for myeloid malignancies. We retrospectively analyzed 200 patients with myeloid malignancies who underwent allo-HCT for the first time. We evaluated CONUT before the initiation of conditioning and compared malnourished patients (poor CONUT, n = 56) with non-malnourished patients (normal CONUT, n = 144). The cumulative incidence of non-relapse mortality within 100 days (early NRM) was significantly higher in the poor CONUT group than in the normal CONUT group [21.4% (95% CI: 11.8-33.0%) vs. 9.7% (95% CI: 5.6-15.2%); P = 0.025]. In multivariate analysis, poor CONUT was an independent and significant risk factor for early NRM [HR: 2.2 (95% CI: 1.0-4.7); P = 0.048]. The overall 1-year survival rate was significantly lower in the poor CONUT group than in the normal CONUT group [53.3% (95% CI: 39.4-65.4%) vs. 71.0% (95% CI: 62.7-77.7%); P = 0.005]. These findings suggest that CONUT before allo-HCT is a useful predictor of poor outcomes in patients with myeloid malignancies.

Stereoselective trimethylsilylation of α- and ß-galactopyranoses.

Trimethylsilylation of the anomeric hydroxyl groups of tetra-O-benzyl and tetra-O-acetyl galactopyranoses was investigated. Stereoselective formation of ß-trimethylsilyl glycoside (ß-TMS glycoside) of benzyl protected compound was achieved using N-trimethylsilyl diethylamine. In the course of the investigation of the selective synthesis of TMS galactosides using TMS-imidazole, we observed the formation of an intermediate, which was converted predominantly into α-TMS glycoside after silica gel column chromatography. A reaction of acetylated compound using TMS-trifluoromethanesulfonate-2,6-lutindine selectively yielded α-TMS glycoside.

SRSF1-3 contributes to diversification of the immunoglobulin variable region gene by promoting accumulation of AID in the nucleus.

Activation-induced cytidine deaminase (AID) is essential for diversification of the Ig variable region (IgV). AID is excluded from the nucleus, where it normally functions. However, the molecular mechanisms responsible for regulating AID localization remain to be elucidated. The SR-protein splicing factor SRSF1 is a nucleocytoplasmic shuttling protein, a splicing isoform of which called SRSF1-3, has previously been shown to contribute to IgV diversification in chicken DT40 cells. In this study, we examined whether SRSF1-3 functions in IgV diversification by promoting nuclear localization of AID. AID expressed alone was localized predominantly in the cytoplasm. In contrast, co-expression of AID with SRSF1-3 led to the nuclear accumulation of both AID and SRSF1-3 and the formation of a protein complex that contained them both, although SRSF1-3 was dispensable for nuclear import of AID. Expression of either SRSF1-3 or a C-terminally-truncated AID mutant increased IgV diversification in DT40 cells. However, overexpression of exogenous SRSF1-3 was unable to further enhance IgV diversification in DT40 cells expressing the truncated AID mutant, although SRSF1-3 was able to form a protein complex with the AID mutant. These results suggest that SRSF1-3 promotes nuclear localization of AID probably by forming a nuclear protein complex, which might stabilize nuclear AID and induce IgV diversification in an AID C-terminus-dependent manner.

Evaluation of the effects of a combination of Japanese honey and hydrocolloid dressing on cutaneous wound healing in male mice.

The aim of this study was to evaluate the effect of the combined use of Japanese honey and hydrocolloid dressing (HCD) on cutaneous wound healing. Mice were divided into four groups: the Acacia (Japan) + HCD, Manuka (New Zealand) + HCD, Chinese milk vetch (Japan) + HCD, and HCD (control) groups. The mice received two full-thickness wounds. The wounds of the HCD group were covered with HCD, whereas those of the other groups were treated with 0.1 mL of the relevant type of honey, before being covered with HCD. Wound area was significantly smaller in the HCD group than in the Acacia + HCD and Manuka + HCD groups on day 13 and days 8-14, respectively. Moreover, compared with the HCD group, reepithelialization was delayed in the Acacia + HCD group and reepithelialization and collagen deposition were delayed in the Chinese milk vetch + HCD and Manuka + HCD groups. These results indicate that the combined use of Japanese honey and HCD does not promote cutaneous wound healing compared with the use of HCD alone. Thus, this method is probably not useful for promoting healing.